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Silver Spring, MD, United States

Permutt T.,Center for Drug Evaluation and Research
Statistics in Medicine | Year: 2016

The National Research Council Panel on Handling Missing Data in Clinical Trials recommended that protocols for clinical trials ‘explicitly define.. causal estimands of primary interest’. In discussions with sponsors of clinical trials since the publication of the National Research Council report, the expression causal estimands has been the subject of confusion. It may not be entirely clear what the National Research Council panel meant, and in any case, it has not been clear how this recommendation might be put in practice. This paper's purpose is to say how the working group understands it and how we think it should be put in practice. We classify possible choices of estimand according to their usefulness for regulatory purposes in various clinical settings. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.


Permutt T.,Center for Drug Evaluation and Research
Statistics in Medicine | Year: 2016

The National Research Council Panel on Handling Missing Data in Clinical Trials recommended that sensitivity analyses have to be part of the primary reporting of findings from clinical trials. Their specific recommendations, however, seem not to have been taken up rapidly by sponsors of regulatory submissions. The NRC report's detailed suggestions are along rather different lines than what has been called sensitivity analysis in the regulatory setting up to now. Furthermore, the role of sensitivity analysis in regulatory decision-making, although discussed briefly in the NRC report, remains unclear. This paper will examine previous ideas of sensitivity analysis with a view to explaining how the NRC panel's recommendations are different and possibly better suited to coping with present problems of missing data in the regulatory setting. It will also discuss, in more detail than the NRC report, the relevance of sensitivity analysis to decision-making, both for applicants and for regulators. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. Published 2015. This article is a U.S. Government work and is in the public domain in the USA


Thompson A.,Center for Drug Evaluation and Research
Nature Reviews Nephrology | Year: 2012

Surrogate end points have the potential to facilitate drug development because effects on surrogate end points can sometimes be demonstrated more rapidly and in smaller studies than can effects on clinical outcomes of interest. Proteinuria has been repeatedly proposed as a surrogate end point for renal outcomes in drug development; however, the FDA has generally not accepted effects on proteinuria as evidence of a drug's effectiveness. Proteinuria is an early marker of some kidney diseases and increases in proteinuria can predict risk of disease progression. Whether or not treatment effects on proteinuria can reliably predict treatment effects on renal outcomes is not known. Nevertheless, it may be reasonable to use effects on proteinuria as a basis for accelerated approval of a drug if certain conditions are met. Approval under this pathway carries with it a requirement to complete a study after drug approval that verifies the anticipated treatment benefit. © 2012 Macmillan Publishers Limited. All rights reserved.


Johannesen L.,Center for Drug Evaluation and Research
Computing in Cardiology | Year: 2011

An algorithm to determine quality of ECGs can enable inexperienced nurses and paramedics to record ECGs of sufficient diagnostic quality. We propose an algorithm that can assess the quality of an ECG designed for an Android-based platform. The algorithm is based on previously established ECG quality metrics for quantifying ECG quality but designed in a way to make it efficient to run on a mobile platform. Using the training data set the proposed algorithm obtained a sensitivity of 91% and a specificity of 85%. Testing against the test data sets, resulted in a score of 0.88 (events 1 and 2) and 0.79 (events 3). The proposed algorithm discriminates between ECGs of good and bad quality, which could help diagnose patients earlier and reduce associated treatment costs. © 2011 CCAL.


Reynolds K.S.,Center for Drug Evaluation and Research
Clinical Pharmacology and Therapeutics | Year: 2012

Individualized therapy is the practice of tailoring therapeutic intervention to a patients disease, demographic characteristics, genetics, environment, lifestyle, and health status. In addition to previous methods of individualization, individualization based on pharmacogenomics is an emerging practice. Although tools are available to aid the determination of the need to individualize therapy, there are barriers to implementation. Various institutions have instituted programs to demonstrate the benefit of individualization, including programs that involve preemptive genotyping. © 2012 American Society for Clinical Pharmacology and Therapeutics.

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